Anticancer agents

ABSTRACT

Disclosed herein is a method for suppressing the growth of cancer cells in a mammal in need of such treatment comprising administering to said mammal a cancer cell suppressing amount of a diphenylmethylpiperazine represented by the following general formula [1]:                    
     wherein R represents:                    
     or a pharmaceutically acceptable salt thereof. 
     Compared with conventional anticancer agents, these agents are less toxic and exert an excellent carcinostatic effect on various solid cancers. Moreover, these anticancer agents inhibit the proliferation of fibroblasts, which makes them efficacious against pulmonary fibrosis and proliferative keloid lesions.

TECHNICAL FIELD

The present invention relates to an anticancer agent, i.e. ananti-malignant tumor agent, for suppressing cancer growth, and moreparticularly, to an anticancer agent, i.e. an anti-malignant tumoragent, containing diphenylmethylpiperazine derivatives and forsuppressing the growth of cancer cells of mammals including human. Thepresent invention also relates to a fibrosis inhibitor for treatingproliferative lesions of pulmonary fibrosis (fibroid lung) disease dueto fibroblastic proliferation and pulmonary fibrosis disease due tofibroblastic proliferation as side effects of anticancer agents, andmore particularly, to a fibrosis inhibitor containingdiphenylmethylpiperazine derivatives and for treating proliferativelesions of mammals including human.

BACKGROUND ART

Anticancer agents or anti-malignant tumor agents include (1) a nitrogenmustard group, such as melphalan, mechlorethamine and cyclophosphamide,(2) a nitrosourea group, such as BCNU, CCNU, methyl-CCNU and ACNU, (3)an azirine group and an epoxide group, such as thiotepa, mitomycin AZQ,carboquone, dianhydrogalactitol and dibromodulcitol, (4) alkylatingagents, such as procarbazine, dacarbazine, and hexamethylenmelamin, (5)antimetabolites including methotrexate (MTX), 6-mercaptopurine (6-MP),6-thioguanine (6-TG), and 5-fluoropyrimidine such as 5-fluorouracil(5-FU), tegafur, UFT, 5′-DFUR and HCFU, and analogue compounds thereof,(6) anticancer agents derived from plants including vinca alkaloidcompounds such as vincristine, vinblastine and vindesine, etoposidecompounds such as etoposide and teniposide, a taxane group such aspaclitaxel and docetaxel, and camptothecin compounds such as irinotecan,(7) anticancer antibiotics such as adriamycin, serbidine, actinomycineD, cosmegen, preno-xanthan, mutamycin, metamycin, and novantron, (8)hormone agents such as adeno-corticoid, estrogen, progesterone,antiestrogen, aromatase inhibitor, androgen, antiandrogen and LH-RHanalogues, (9) enzymes such as L-asparaginase, (10) platinum complexcompounds such as cisplatin, carboplatin and nedaplatin (254-S), (11)nonspecific immunostimulants, (12) interferon, and (13) a TNF group.

Along with the establishment of medical treatments by the use of theseanticancer agents, a patient of acute lymphatic leukemia, Hodgkin'sdisease or the like has had considerably high possibility of returningto social life. However, a patient involved with solid cancers, such asgastric cancer, lung cancer and colon cancer, largely relies uponsurgical and radiation treatments. Cisplatin has been used in thetreatments of these solid cancers because of its broad antitumorspectrum. However, cisplatin has a problem of confirmed toxicities, suchas nephrotoxicity, gastrointestinal toxicity, auditory toxicity andperipheral nerve toxicity, and its low cure rate.

Further, it is known that some anticancer agents superinduce pulmonaryfibrosis as side effects, which has serious impact on life prognosis.

It is an object of the present invention to solve these problems of theanticancer agents.

It is an object of the present invention to provide compounds, saltsthereof and derivatives thereof, which have a property of exhibiting asignificant anticancer activity (or anti-malignant tumor activity)against various cancers or suppressing proliferation of pulmonaryfibroblast, or combinedly have both properties of exhibiting asignificant anticancer activity (or anti-malignant tumor activity)against various cancers and suppressing proliferation of pulmonaryfibroblast, as well as a desirable low toxicity.

DISCLOSURE OF INVENTION

The inventors have discovered that compounds represented by thefollowing general formula [1];

wherein R represents;

salts thereof, derivatives thereof or prodrugs thereof have a lesstoxicity than that of cisplatin, and have a greater carcinostatic effecton various cancers and fibroblastic proliferation suppressing effectthan those of cisplatin, and have then completed the present invention.

That is, the present invention is an anticancer agent containing acompound represented by the following general formula [1];

wherein R represents;

a salt thereof, a derivative thereof or a prodrug thereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing a cell-proliferation suppressing actionagainst fibroblast of the compound represented by the above generalformula [1] and the like shown in Example 2.

BEST MODE FOR CARRYING OUT THE INVENTION

A compound represented by the following general formula [1];

wherein R represents;

(hereinafter referred to as “the compound represented by the abovegeneral formula [1]”), a salt thereof, a derivative thereof or a prodrugthereof (hereinafter, all together, referred to as “the compoundrepresented by the above general formula [1] and the like) and a methodfor manufacturing the same of the present invention are disclosed in:International Patent Laid-Open Publication WO-92/00962 and JapanesePatent Laid-Open Publication No. Hei 4-69377 (hereinafter referred to as“the above publications”).

The above publications further disclose that the compound represented bythe above general formula [1] and the like have an action of suppressingmyocardial hypercontraction and hyperextension to protect cardiac musclemyocardium from necrosis without any cardiac depression action, and havean effect of curing and preventing cardiac infarction as well as aneffect of suppressing and preventing myocardial necrosis.

The inventors have discovered that, compared with cisplatin and otheranticancer agents, the compound represented by the above general formula[1] and the like have a superior anticancer action against variouscancers and exhibit a broader anticancer spectrum against variouscancers in vivo and in vitro. The inventors have also discovered thatthe compound represented by the above general formula [1] and otherssuppressed proliferation of fibroblasts.

In the present invention, the term “anticancer agent” encompasses anycures or therapeutic agents of cancers, and/or any fibrosis inhibitorsor suppressors.

In the present invention, the “salt” of the compound represented by theabove general formula [1] means any pharmaceutically acceptable salts,and includes, but is not limited to, inorganic acid addition salts suchas hydrochloride, hydrobromide, sulfate, phosphate or nitrate; organicacid addition salts such as acetate, propionate, succinate, glycolate,lactate, malate, oxalate, tartrate, citrate, maleate, fumarate,methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate; oramino acid addition salts, such as aspartate or glutamate, as well ashydrated substances and hydrates.

In the present invention, the “prodrug” of the compound represented bythe above general formula [1] is any derivative of the compoundrepresented by the above general formula [1], in which the derivativehas a chemically or metabolically degradable group, and exhibits anactivity as an anticancer agent by hydrolysis or solvolysis or bydegradation under physiological conditions.

The compound represented by the above general formula [1] and the likeaccording to the present invention has an excellent carcinostaticeffect. More specifically, the anticancer agent according to the presentinvention contains at least one of the compounds represented by theabove general formula [1] and the like as a principal agent. Theanticancer agent of the present invention can be administered togetherwith any other suitable anticancer agent to bring out an enhancedcarcinostatic action even against cancers having an acquired resistance.When used as an anticancer agent, the compound represented by the abovegeneral formula [1] and the like may be typically administeredsystemically or locally, or orally or parenterally. The anticancer agentof the present invention may be administered simultaneously with anyother suitable anticancer agent, or before or after such otheranticancer agent is administered.

While the dosage of the anticancer agent is varied according to age,weight, symptom, therapeutic effect, way of administration, treatmenttime or the like, the anticancer agent is typically administered in therange of 0.01 mg to 1 g, preferably in the range of 100 to 500 mg, peradult (average weight of 60 kg), orally or parenterally once a day or inseveral divided doses a day. In the parenteral administration, theanticancer agent may be continuously administered over 12 hours or more.

When a solid composition for oral administration is prepared by usingthe compound represented by the above general formula [1] and the likeof the present invention as a principal agent, the solid composition maybe formed in any suitable dosage form, such as tablet, pill, powder orgranule. In such a solid composition, one or more principal agents maybe mixed with one or more active diluents, dispersants, adsorbents orthe like, such as lactose, mannitol, glucose, hydroxypropylcellulose,microcrystalline cellulose, starch, polyvinylpyrolidone, magnesiumaluminometasilicate or silicic acid anhydride powder. Further, thecomposition may be mixed with any suitable additive other than thediluents in the usual manner.

For preparing the tablet or pill by using the compound represented bythe above general formula [1] and the like of the present invention as aprincipal agent, the tablet or pill may be coated with a film made of agastric-soluble or enteric-soluble substance, such as saccharose,gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, ormay be coated with two or more layers, according to need. Further, thetablet or pill may be capsuled by any suitable substance such as gelatinor ethylcellulose.

When a liquid composition for oral administration is prepared by usingthe compound represented by the above general formula [1] and the likeof the present invention as a principal agent, the liquid compositionmay be formed in any suitable pharmaceutically acceptable dosage form,such as emulsion, solution, suspension, syrup or elixir. In this case, adiluent to be used includes, for example, purified water-ethanol,vegetable oil or emulsifier or the like. In addition to the diluent,such a composition may be mixed with an adjuvant, such as a moisteningagent, suspension, edulcorant, flavoring ingredient, aromatic substanceor antiseptic.

When a solution for injection for parenteral administration is preparedby using the compound represented by the above general formula [1] andthe like of the present invention, a sterile aqueous or non-aqueoussolution, solubilizing agent, suspension or emulsifier may be used. Theaqueous solution, solubilizing agent or suspension includes, forexample, water for injection, distilled water for injection,physiological salt solution, cyclodextrin and derivatives thereof, anorganic amine group such as triethanolamine, diethanolamine,monoethanolamine or triethylamine, or an inorganic alkali solution.

For preparing the water-soluble solution by using the compoundrepresented by the above general formula [1] and the like of the presentinvention, for example, propylene glycol or polyethylene glycol; orvegetable oil such as olive oil; or alcohol such as ethanol may be used.Further, the solubilizing agent includes, for example, a surface-activeagent (for forming mixed micelle) such as polyoxyethylene hydrogenatedcastor oil, or saccharose fatty acid ester; or lecithin or hydrogenatedlecithin (for forming liposome). Further, an emulsion formulation may beformed by composed of non-aqueous solvent such as vegetable oil, andlecithin, polyoxyethylene hydrogenated castor oil,polyoxyethylene-polyoxypropyleneglycol or the like.

Other compositions for parenteral administration may be formed in aliniment such as ointment, a suppository, a pessary or the like, whichcontains one or more principal agents, i.e. the compound represented bythe above general formula [1] and the like, and is prescribed accordingto a known method.

EXAMPLES

Examples of a formulation using the compound represented by the abovegeneral formula [1] and the like of the present invention as a principalagent of an anticancer agent will be specifically described below.However, this invention is not limited by the following description.

Example 1

An injection formulation of an anticancer agent in this example uses1-[1-4-(diphenylmethyl)piperazinyl]-3-[1-{4-(4-chlorophenyl)-4-hydroxy}piperidinyl]-2-propanol(hereinafter referred to as “compound 1”) as a principal agent.

Examples of synthesizing compound 1 will be described below. In thefollowing description, the nuclear magnetic resonance spectrum (NMR) ismeasured by using tetramethylsilane as an internal standard, and isexpressed by ppm. The unit “part” means “volume part”.

(1) Synthesis of 1-(Diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine

After 1-(diphenylmethyl)piperazine (10.0 g) was dissolved inacetonitrile (50 ml), sodium carbonate (6.5 g) and epibromohydrin (6.8g) were added thereto, and the mixture was heated under reflux for 2.5hours. Salts were separated by filtration, and then the resultingfiltrate was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (Wako gel C-200, 200 g)and eluted with a mixed solvent of 99 parts of chloroform and 1 part ofmethanol to obtain 1-(diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine(5.9 g).

Nuclear Magnetic Resonance Spectrum

¹H-NMR (CDC13, 500 MHz) δ: 2.30-2.80 (12H, m), 3.06-3.10 (1H, s), 4.23(1H, s), 7.16 (2H, t, J=7.3 Hz), 7.25 (4H, t, J=7.3 Hz), 7.40 (4H, d,J=7.3 Hz).

(2) Synthesis of1-{1-4-(Diphenylmethyl)piperazinyl}-3-[1-{4-(4-chlorophenyl)-4-hydroxy}piperidinyl]-2-propanol

1-(diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine (3.0 g) and4-(4-chlorophenyl)-4-hydroxypiperidine (2 g) were dissolved ino-dichlorobenzene (20 ml), and heated under reflux for 2.5 hours. Afterstanding to cool, the mixture was purified by silica gel columnchromatography (Wako gel C-200, 100 g) to obtain 4.6 g of1-{1-4-(diphenylmethyl)piperazinyl}-3-(1-{4(4-chlorophenyl)-4-hydroxy}-piperidinyl]-2-propanol(compound 1).

Infrared Absorption Spectrum: IR νmax (cm−1) KBr: 3300, 2950, 2650,1620, 1450, 1100, 910, 830, 750, 710 (as hydrochloride)

Nuclear Magnetic Resonance Spectrum

¹H-NMR (CDC13, 500 MHz) δ: 1.50˜1.90 (4H, m), 2.01˜2.21 (2H, m),2.30˜2.55 (10H, m), 2.80˜2.90 (2H, m), 3.87˜3.93 (1H, m), 4.22 (1H, s),7.16 (2H, t, J=7.3 Hz), 7.26 (4H, t, J=7.3 Hz), 7.30 (2H, d, J=8.5 Hz),7.40 (4H, d, J=7.3 Hz), 7.42 (2H, d, J=8.5 Hz).

FD Mass Spectrum

FD-MS (m/z): 519, 521 (M+).

(1) Injection Formulation of Compound 1 compound 1 2-40 mg D-sorbitol1000 mg citric acid 10 mg sodium hydroxide optimum dose water forinjection to obtain 20.0 ml of solution by adding water for injection

D-sorbitol and citric acid were dissolved in a sufficient amount ofwater for injection. Compound 1 was dissolved in the obtained solution,and the resulting solution was adjusted to pH 3.2-3.3 by adding sodiumhydroxide. Then, the remaining water for injection was added theretounder agitation. This solution was filtered and then hermetically filledinto an ampoule of 20 ml. The contents of the ampoule were sterilized inan autoclave.

(2) Verification of In Vitro Antitumor Effects on Various Human CancerCell Lines According to the MTT Assay Method.

Each single cell of a human non-small-cell lung cancer cell line PC-14,a human non-small-cell lung cancer cell line SBC-3, a humannon-small-cell mammary cancer cell line MCF-7, a human non-small-cellovarian cancer cell line SKOV3, a human leukemia cell line HL60 and ahuman colon cancer cell line WiDR was obtained by trypsinization or byusing a cell scraper in RPMI 1640 medium to prepare a suspensioncontaining 100 cells per 15 μl. The compound 1 as an anticancer agentwas dissolved in dimethylsulfoxide and then the solution was added tothe suspension to make the concentration of the compound fall within arange between 0.5 and 1 μM, and the resulting suspension was poured intoa 96-perforated plate at 150 μl/well. This plate was maintained at atemperature of 37° C. under 5% of carbon dioxide and saturated vapor for96 hours to incubate the suspension. After incubation, the incubatedsuspension was combined with 20 μl of MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) reagentdissolved in D-PBS (−) at a concentration of 5 mg/ml, and was furtherincubated at 37° C. for 4 hours. After the completion of incubation, theentire plate was centrifuged to discharge supernatant. Then, 200 μl ofdimethyl sulfoxide was added to dissolve purple formazan which iscreated from yellow MTT by the action of dehydrogenase lying inmitochondria in the cancer cell, and the amount of the created formazanwas determined by reading the absorbance at a wave length ranging from562 to 630 nm with a multi-plate reader. Given that the average growthrate of a negative control is 0% and the average growth rate of apositive control is 100%, a tumor-volume growth curve was plotted, andthe concentration of compound 1 required for 50% of human cancer-cellproliferation suppression was calculated. This is shown in Table 1.

TABLE 1 amount of compound 1 required to achieve IC₅₀ cell line (μM)PC-14 1.02 ± 0.20 (human non-small-cell lung cancer cell line)SBC-3(human small-cell lung cancer cell line) 0.46 ± 0.03 MCF-7 (humanmammary cancer cell line) 0.60 ± 0.08 SKOV3 (human ovarian cancer cellline) 0.85 ± 0.02 HL60 (human leukemia cell line) 1.18 ± 0.05 WiDR(human colon cancer cell line) 0.41 ± 0.03

The values in Table 1 indicate each value of the concentration requiredfor 50% of human cancer-cell proliferation suppression from the MTTassay in triple culture tests of independent cancer cells using compound1 by average±error range (μM).

As shown in Table 1, the compound 1 shows the 50% proliferationsuppression effect (IC₅₀) against various cancers at a concentrationranging from 0.5 to 1.1 μM. This IC₅₀ value of compound 1 issignificantly lower than the IC₅₀ value ranging from 2 to 3 μM in theMTT assay method of cisplatin which has been considered as the mosteffective agent against solid cancers. According to the IC₅₀ of compound1, it is proved that compound 1 has an enhanced carcinostatic effect andeffectiveness as an anticancer agent. In addition, compound 1 exhibitssubstantially equal antitumor effects on solid cancer cells such as lungcancer, mammary cancer, colon cancer, ovarian cancer, as well asleukemia cells. This means that compound 1 has a broad antitumorspectrum.

Example 2

Nine plates were prepared for each of control and compound 1 groups eachhaving a concentration of 1×10⁻⁶ M and a compound 1 group having aconcentration of 3×10⁻⁶ M (total of 27 plates). The number 4.4×10⁵ offibroblasts NIH3T3 were added to each of the 27 plates, and D-MEMculture solution added with 10% FBS (fetal bovine serum) was addedthereto. Each of the controls was incubated with added watercorresponding to the added amount of compound 1. The number of cells in3 plates of each of the groups was measured every 24 hours, and themeasured numbers were averaged to provide an average cell number perplate. The results are shown in FIG. 1. As shown in the results, thecompound 1 has an effective anticancer action and effectiveness toproliferative lesions such as interstitial pneumonia and keloid due toproliferation of fibroblasts.

Example 3

A physiological saline suspension was made by adding 2×10⁷ cells ofhuman non-small-cell lung cancer cell line PC-14, and was then implantedsubcutaneously to the back of female nude mice BALB/c nu/nu (6 weeks).Then, progress of take was observed. The seventh day after theimplantation, the tumor state was checked to select testable mice. Theselected mice were randomized to avoid deviation, and divided into acontrol group, a first subject group and a second subject group eachcomposed of 6 mice. Each tumor volume of the implanted tumors wasdetermined by measuring the minor axis and the major axis of each tumorand then calculating the product of square of the minor axis of thetumor and the major axis of the tumor, i.e. using the formula: (theminor axis of the tumor)²×(the major axis of the tumor). From theseventh day after the tumor implantation, the administration of thecompound 1 was started.

1.2 mg of the compound 1 was dissolved in 0.05 ml of dimethyl sulfoxide,and 0.95 ml of solution consisting of 5% sorbitol-0.2% citric acid 1hydrate (pH 3.3) was added thereto to form a uniform solution as asolution for injection.

For six subjects of the group number 1, the compound 1 was administeredby injecting from each tail of the nude mice on each of the 7th, 8th,10th and 11th days after the implantation, at 3 mg of the compound 1 perkg of weight once a day. For six subjects of the group number 2, thecompound 1 was administered by injecting from each tail of the nude miceon each of the 7th, 8th, 10th and 11th days after the implantation, at 5mg of the compound 1 per kg of weight once a day. The subjects of thegroup number 1 to be the controls were a group having no administrationof the compound 1, and neither administration nor treatment of thecompound 1 was performed on the controls. For all of the subjects, thestate of each entire body of the mice was observed to measure eachweight and tumor volume of the mice, once a day from the 1st day to the8th day after the administration of compound 1, before the compound 1was administered. In the result of the observation of each entire bodystate of the mice and the measurement of each weight of the mice,substantially no difference was found between the subjects of the groupnumbers 1 to 3. However, in the result of each tumor volume of the mice,a specific difference was found between the subjects of the groupnumbers 1 to 3. The measurement of the tumor volumes is shown in thefollowing Table 2, and the average of the tumor volumes in each of thegroups is shown in Table 3. In Tables 2 and 3, each size of the tumorvolumes after the 2nd day is represented on condition that the size ofthe tumor volume on the 1st day is 100.

TABLE 2 group subject No. No 1 day 2 day 3 day 4 day 5 day 6 day 7 day 8day 1 1 100.00 111.45 148.16 179.50 233.01 208.06 230.37 290.31 1 2100.00 145.96 116.07 117.73 107.15 61.17 108.09 131.77 1 3 100.00 103.1571.62 72.94 74.51 55.21 72.46 60.61 1 4 100.00 169.32 143.35 149.41205.18 214.09 221.72 265.04 1 5 100.00 91.66 140.09 114.08 111.79 188.97165.66 182.55 1 6 100.00 131.69 147.32 85.63 132.46 87.52 113.77 127.272 1 100.00 45.35 20.22 46.17 31.44 30.93 52.68 56.49 2 2 100.00 120.5198.14 80.18 66.58 122.90 99.04 127.45 2 3 100.00 139.67 85.27 105.0167.76 55.16 75.58 130.56 2 4 100.00 73.21 52.91 42.19 22.55 0.00 0.000.00 2 5 100.00 73.29 62.47 31.02 18.55 10.11 12.98 4.97 2 6 100.0066.68 83.06 85.73 51.09 51.30 47.68 30.49 3 1 100.00 55.40 58.27 79.3447.44 33.96 34.07 47.99 3 2 100.00 63.47 43.51 40.73 40.65 32.21 36.2715.80 3 3 100.00 93.53 72.22 83.65 62.95 54.93 86.76 102.87 3 4 100.0068.25 113.73 123.79 103.32 135.18 129.59 140.33 3 5 100.00 90.42 70.2336.86 28.95 14.65 17.36 7.22 3 6 100.00 80.68 92.68 84.55 79.20 51.9685.12 61.54

TABLE 3 group average No. (6 mice) 1 day 2 day 3 day 4 day 5 day 6 day 7day 8 day 1 1 100.00 121.23 124.35 121.20 147.83 143.83 159.88 165.10 22 100.00 89.79 67.01 68.38 46.68 47.73 42.99 58.33 3 3 100.00 78.6375.11 74.99 60.45 53.82 64.86 62.63

1-{1-4-(Diphenylmethyl)piperazinyl}-3-[1-{4-(4-chlorophenyl)-4-hydroxy}piperidinyl]-2-propanol

In view of the results of the examples 1 to 3, it is proved that thecompound 1 has a high carcinostatic effect.

While the compound 1 of1-{1-4-(diphenylmethyl)piperazinyl}-3-[1-{4-(4-chlorophenyl)-4-hydroxy}piperidinyl]-2-propanolwas used as a principal agent in the above examples 1 to 3,1-{2-(1,2,3,4-tetrahydro)isoquinolinil}-3-{1-(4-diphenylmethyl)piperidinyl}-2-propanolwas used as a principal agent to obtain the same result.

A example of synthesizing1-{2-(1,2,3,4-tetrahydro)isoquinolinil}-3-{1-(4-diphenylmethyl)piperidinyl}-2-propanolwill be described bellow. In the following description, a nuclearmagnetic resonance spectrum (NMR) is measured by using tetrametylsilaneas an internal standard, and expressed by ppm. The unit “part” means“volume part”.

Example 4 (1) Synthesis of2-{1-(2,3-Epoxy)propyl}-1,2,3,4-tetrahydroisoquinoline

1,2,3,4-tetrahydroisoquinoline (25.0 g) was dissolved in acetonitrile(100 ml), and sodium carbonate (40.0 g) and epibromohydrin (31.0 g) wereadded thereto. Then, the mixture was heated under reflux for 4 hours.After separating salts in the mixture by filtration, the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (Wako gel C-200, 500 g), and thenwas eluted with a mixed solvent of 99 parts of chloroform and 1 part ofmethanol to obtain 2-{1-(2,3-epoxy)propyl}-1,2,3,4-tetrahydroisoquinoline (15.6 g).

Nuclear Magnetic Resonance Spectrum

¹H-NMR (CDC13, 100 MHz) δ: 2.36˜2.60 (2H, m), 2.73˜3.03 (6H, m),3.09˜3.29 (1H, m), 3.65 (1H, d, J=14.9 Hz), 3.83 (1H, d,).

(2) Synthesis of1-{2-(1,2,3,4-Tetrahydro)isoquinolinil}-3-{1-(4-diphenylmethyl)piperazinyl}-2-propanol

2-{1-(2,3-epoxy)propyl}-1,2,3,4-tetrahydroisoquinoline (3.0 g) and1-(diphenylmethyl)piperazine (4.4 g) were dissolved in o-dichlorobenzene(20 ml), and heated under reflux for 2.5 hours. After standing to cool,the mixture was purified by silica gel column chromatography (Wako gelC-200, 150 g) to obtain1-{2-(1,2,3,4-tetrahydro)isoquinolinyl}-3-{1-(4-diphenylmethyl)piperazinyl}-2-propanol(6.0 g).

Infrared Absorption Spectrum: IR νmax (cm−1) KBr: 3400, 3000, 2550,1620, 1450, 1080, 920, 760, 710 (as hydrochloride).

Nuclear Magnetic Resonance Spectrum

¹H-NMR (CDC13, 100 MHz) δ: 2.30˜2.60 (1.2H, m), 2.75˜2.95 (4H, m),3.62˜3.80 (2H, m), 3.92˜4.03 (1H, m), 4.21 (1H, s), 7.00˜7.51 (14H, m).

FD Mass Spectrum

FD-MS (m/z): 441 (M+).

INDUSTRIAL APPLICABILITY

The compound represented by the above general formula [1] and the likeaccording to the present invention have a less toxicity than that of theconventional anticancer agents such as cisplatin, and exhibits a greatercarcinostatic action against various cancers and a broader carcinostaticspectrum than that of the conventional anticancer agents. Thus, comparedwith the conventional anticancer agents, the present invention will makea greater contribution to treatments of cancers (solid cancers) andother malignant tumors. Further, the present invention has an action ofsuppressing proliferation of fibroblasts such as pulmonary fibrosis, andhas an excellent fibrosis suppressing action superior to theconventional curatives of pulmonary fibrosis, keloid or the like. Thus,the present invention will make a greater contribution to treatments ofpulmonary fibrosis or keloid.

What is claimed is:
 1. A method for suppressing the growth of cancercells in a mammal in need of such treatment comprising administering tosaid mammal a cancer cell suppressing amount of adiphenylmethylpiperazine represented by the following general formula[1]:

wherein R represents:

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the diphenylmethylpiperazine is1-{1-4-(diphenylmethyl)piperazinyl}-3-[1-{4-(4-chlorophenyl)-4-hydroxy}piperidinyl]-2-propanol.3. The method of claim 1, wherein the diphenylmethylpiperazine is1-{2-(1,2,3,4-tetrahydro)isoquinolinyl}-3-{1-(4-diphenylmethyl)piperazinyl}-2-propanol.4. A method for treating proliferative lesions of pulmonary fibrosisdisease in a mammal in need of such treatment comprising administeringto said mammal a fibrosis inhibiting amount of adiphenylmethylpiperazine represented by the following general formula[1]:

wherein R represents:

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 4,wherein the diphenylmethylpiperazine is1-{1-4-(diphenylmethyl)piperazinyl}-3-[1-{4-(4-chlorophenyl)-4-hydroxy}piperidinyl]-2-propanol.6. The method of claim 4, wherein the diphenylmethylpiperazine is1-{2-(1,2,3,4-tetrahydro)isoquinolinyl}-3-{1-(4-diphenylmethyl)piperazinyl}-2-propanol.